Articles on Medical Diseases and Conditions

Tag: Cushing’s syndrome

  • Laboratory Tests in Psychiatry

    Until recently, the laboratory had relatively little to offer in psychiatry. Laboratory tests were used mainly to diagnose or exclude organic illness. For example, in one study about 5% of patients with dementia had organic diseases such as hyponatremia, hypothyroidism, hypoglycemia, and hypercalcemia; about 4% were caused by alcohol; and about 10% were due to toxic effects of drugs. A few psychiatric drug blood level assays were available, of which lithium was the most important. In the 1970s, important work was done suggesting that the neuroendocrine system is involved in some way with certain major psychiatric illnesses. Thus far, melancholia (endogenous psychiatric depression or primary depression) is the illness in which neuroendocrine abnormality has been most extensively documented. It was found that many such patients had abnormal cortisol blood levels that were very similar to those seen in Cushing’s syndrome (as described in the chapter on adrenal function) without having the typical signs and symptoms of Cushing’s syndrome. There often was blunting or abolition of normal cortisol circadian rhythm, elevated urine free cortisol excretion levels, and resistance to normally expected suppression of cortisol blood levels after a low dose of dexamethasone.

    Because of these observations, the low-dose overnight dexamethasone test, used to screen for Cushing’s syndrome, has been modified to screen for melancholia. One milligram of oral dexamethasone is given at 11 P.M., and blood is drawn for cortisol assay on the following day at 4 P.M. and 11 P.M. Normally, serum cortisol levels should be suppressed to less than 5 µg/100 ml (138 nmol/L) in both specimens. An abnormal result consists of failure to suppress in at least one of the two specimens (about 20% of melancholia patients demonstrate normal suppression in the 4 P.M. specimen but no suppression in the 11 P.M. specimen, and about the same number of patients fail to suppress in the 4 P.M. specimen but have normal suppression in the 11 P.M. sample). The psychiatric dexamethasone test is different from the dexamethasone test for Cushing’s syndrome, because in the Cushing protocol a single specimen is drawn at 8 A.M. in the morning after dexamethasone administration.

    The Cushing’s disease protocol is reported to detect only about 25% of patients with melancholia, in contrast to the modified two-specimen psychiatric protocol, which is reported to detect up to 58%. Various investigators using various doses of dexamethasone and collection times have reported a detection rate of about 45% (literature range, 24%-100%). False positive rates using the two-specimen protocol are reported to be less than 5%. Since some patients with Cushing’s syndrome may exhibit symptoms of psychiatric depression, differentiation of melancholia from Cushing’s syndrome becomes necessary if test results show nonsuppression of serum cortisol. The patient is given appropriate antidepressant therapy and the test is repeated. If the test result becomes normal, Cushing’s syndrome is virtually excluded.

    Various conditions not associated with either Cushing’s syndrome or melancholia can affect cortisol secretion patterns. Conditions that must be excluded to obtain a reliable result include severe major organic illness of any type, recent electroshock therapy, trauma, severe weight loss, malnutrition, alcoholic withdrawal, pregnancy, Addison’s disease, and pituitary deficiency. Certain medications such as phenobarbital, phenytoin (Dilantin), steroid therapy, or estrogens may produce falsely abnormal results.

    At present, there is considerable controversy regarding the usefulness of the modified low-dose dexamethasone test for melancholia, since the test has a sensitivity no greater than 50% and significant potential for false positive results.

    Besides the overnight modified low-dose dexamethasone test, the thyrotropin-releasing hormone (TRH) test has been reported to be abnormal in about 60% of patients with primary (unipolar) depression. Abnormality consists of a blunted (decreased) thyrotropin-stimulating hormone response to administration of TRH, similar to the result obtained in hyperthyroidism or hypopituitarism. However, occasionally patients with melancholia have hypothyroidism, which produces an exaggerated response in the TRH test rather than a blunted (decreased) response.

    One investigator found that about 30% of patients with melancholia had abnormal results on both the TRH and the modified dexamethasone tests. About 30% of the patients had abnormal TRH results but normal dexamethasone responses, and about 20% had abnormal dexamethasone responses but normal TRH responses. The TRH test has not been investigated as extensively as the modified dexamethasone test.

    A more controversial area is measurement of 3-methoxy-4-hydroxyphenylglycol (MHPG) in patients with depression. One theory links depression to a functional deficiency of norepinephrine in the central nervous system (CNS). 3-Methoxy-4-hydroxyphenylglycol is a major metabolite of norepinephrine. It is thought that a significant part of urinary MHPG is derived from CNS sources (20%-63% in different studies). Some studies indicated that depressed patients had lower urinary (24-hour) excretion of MHPG than other patients, and that patients in the manic-phase of bipolar (manic-depressive) illness had increased MHPG levels. There was also some evidence that depressed patients with subnormal urinary MHPG levels responded better to tricyclic antidepressants such as imipramine than did patients with normal urine MHPG levels. However, these findings have been somewhat controversial and have not been universally accepted.

  • Female Delayed Puberty and Primary Amenorrhea

    Onset of normal puberty in girls is somewhat variable, with disagreement in the literature concerning at what age to diagnose precocious puberty and at what age to suspect delayed puberty. The most generally agreed-on range of onset for female puberty is between 9 and 16 years. Signs of puberty include breast development, growth of pubic and axillary hair, and estrogen effect as seen in vaginal smears using the Papanicolaou stain. Menstruation also begins; if it does not, the possibility of primary amenorrhea arises. Primary amenorrhea may or may not be accompanied by evidence that suggests onset of puberty, depending on the etiology of the amenorrhea. Some of the causes of primary amenorrhea are listed in the box.

    Some Etiologies of Female Delayed Puberty and Primary Amenorrhea
    Mullerian dysgenesis (Mayer-Rokitansky syndrome): congenital absence of portions of the female genital tract, with absent or hypoplastic vagina. Ovarian function is usually normal. Female genotype and phenotype.
    Male pseudohermaphroditism: genetic male (XY karotype) with female appearance due to deficiency of testosterone effect.
    1. Testicular feminization syndrome: lack of testosterone effect due to defect in tissue testosterone receptors.
    2. Congenital adrenal hyperplasia: defect in testosterone production pathway.
    3. Male gonadal dysgenesis syndromes: defect in testis function.
    a. Swyer syndrome (male pure gonadal dysgenesis): female organs present except for ovaries. Bilateral undifferentiated streak gonads. Presumably testes never functioned and did not prevent mьllerian duct development.
    b. Vanishing testes syndrome (XY gonadal agenesis): phenotype varies from male pseudohermaphrodite to ambiguous genitalia. No testes present. Presumably testes functioned in very early embryologic life, sufficient to prevent mьllerian duct development, and then disappeared.
    c. Congenital anorchia: male phenotype, but no testes. Presumably, testes functioned until male differentiation took place, then disappeared.
    Female sex chromosome abnormalities (Turner’s syndrome—female gonadal dysgenesis— and Turner variants): XO karyotype in 75%-80% of patients, mosaic in others. Female phenotype. Short stature in most, web neck in 40%. Bilateral streak gonads.
    Polycystic (Stein-Leventhal) or nonpolycystic ovaries, not responsive to gonadotropins.
    Deficient gonadotropins due to hypothalamic or pituitary dysfunction.
    Hyperprolactinemia: pituitary overproduction of prolactin alone.
    Effects of severe chronic systemic disease: chronic renal disease, severe chronic GI disease, anorexia nervosa, etc.
    Constitutional (idiopathic) delayed puberty: puberty eventually takes place, so this is a retrospective diagnosis.
    Other: Cushing’s syndrome, hypothyroidism, and isolated GH deficiency can result in delayed puberty.

    Physical examination is very important to detect inguinal hernia or masses that might suggest the testicular feminization type of male pseudohermaphroditism, to document the appearance of the genitalia, to see the pattern of secondary sex characteristics, and to note what evidence of puberty exists and to what extent. Pelvic examination is needed to ascertain if there are anatomical defects preventing menstruation, such as a nonpatent vagina, and to detect ovarian masses.

    Laboratory tests

    Basic laboratory tests begin with chromosome analysis, since a substantial minority of cases have a genetic component. Male genetic sex indicates male pseudohermaphroditism and leads to tests that differentiate the various etiologies. Turner’s syndrome and other sex chromosome disorders are also excluded or confirmed. If there is a normal female karyotype and no chromosome abnormalities are found, there is some divergence of opinion on how to evaluate the other important organs of puberty—the ovaries, pituitary, and hypothalamus. Some prefer to perform serum hormone assays as a group, including pituitary gonadotropins (FSH and LH), estrogen (estradiol), testosterone, prolactin, and thyroxine. Others perform these assays in a step-by-step fashion or algorithm, depending on the result of each test, which could be less expensive but could take much more time. Others begin with tests of organ function. In the algorithm approach, the first step is usually to determine if estrogen is present in adequate amount. Vaginal smears, serum estradiol level, endometrial stimulation with progesterone (for withdrawal bleeding), and possibly endometrial biopsy (for active proliferative or secretory endometrium, although biopsy is considered more often in secondary than in primary amenorrhea)—all are methods to detect ovarian estrogen production. If estrogen is present in adequate amount, this could mean intact hypothalamic-pituitary-ovarian feedback or could raise the question of excess androgen (congenital adrenal hyperplasia, Cushing’s syndrome, PCO disease, androgen-producing tumor) or excess estrogens (obesity, estrogen-producing tumor, iatrogenic, self-medication). If estrogen effect is absent or very low, some gynecologists then test the uterus with estrogen, followed by progesterone, to see if the uterus is capable of function. If no withdrawal bleeding occurs, this suggests testicular feminization, congenital absence or abnormality of the uterus, or the syndrome of intrauterine adhesions (Asherman’s syndrome). If uterine withdrawal bleeding takes place, the uterus can function, and when this finding is coupled with evidence of low estrogen levels, the tentative diagnosis is ovarian failure.

    The next step is to differentiate primary ovarian failure from secondary failure caused by pituitary or hypothalamic disease. Hypothalamic dysfunction may be due to space-occupying lesions (tumor or granulomatous disease), infection, or (through uncertain mechanism) effects of severe systemic illness, severe malnutrition, and severe psychogenic disorder. X-ray films of the pituitary are often ordered to detect enlargement of the sella turcica from pituitary tumor or suprasellar calcifications due to craniopharyngioma. Polytomography is more sensitive for sellar abnormality than ordinary plain films. CT also has its advocates. Serum prolactin, thyroxine, FSH, and LH assays are done. It is necessary to wait 4-6 weeks after a progesterone or estrogen-progesterone test before the hormone assays are obtained to allow patient hormone secretion patterns to resume their pretest status. An elevated serum prolactin value raises the question of pituitary tumor (especially if the sella is enlarged) or idiopathic isolated hyperprolactinemia. However, patients with the empty sella syndrome and some patients with hypothyroidism may have an enlarged sella and elevated serum prolactin levels, and the other causes of elevated prolactin levels (see the box) must be considered. A decreased serum FSH or LH level confirms pituitary insufficiency or hypothalamic dysfunction. A pituitary stimulation test can be performed. If the pituitary can produce adequate amounts of LH, this suggests hypothalamic disease (either destructive lesion, effect of severe systemic illness, or malnutrition). However, failure of the pituitary to respond does not necessarily indicate primary pituitary disease, since severe long-term hypothalamic deficiency may result in temporary pituitary nonresponsiveness to a single episode of test stimulation. Hormone therapy within the preceding 4-6 weeks can also adversely affect test results.

    The box lists some conditions associated with primary amenorrhea or delayed puberty and the differential diagnosis associated with various patterns of pituitary gonadotropin values. However, several cautionary statements must be made about these patterns. Clearly elevated FSH or LH values are much more significant than normal or mildly to moderately decreased levels. Current gonadotropin immunoassays are technically more reproducible and dependable at the upper end of usual values than at the lower end. Thus, two determinations on the same specimen could produce both a mildly decreased value and a value within the lower half of the reference range. In addition, blood levels of gonadotropins, especially LH, frequently vary throughout the day. The values must be compared with age- and sexmatched reference ranges. In girls, the levels also are influenced by the menstrual cycle, if menarche has begun. Second, the conditions listed—even the genetic ones, although to a lesser extent—are not homogeneous in regard to severity, clinical manifestations, or laboratory findings. Instead, each represents a spectrum of patients. The more classic and severe the clinical manifestations, the more likely that the patient will have “expected” laboratory findings, but even this rule is not invariable. Therefore, some patients having a condition typically associated with an abnormal laboratory test result may not show the expected abnormality. Laboratory error is another consideration. Also, the spectrum of patients represented by each condition makes it difficult to evaluate reports of laboratory findings due to differences in patient population, severity of illness, differences in applying diagnostic criteria to the patients, variance in specimen collection protocols, and technical differences in the assays used in different laboratories. In many cases, adequate data concerning frequency that some laboratory tests are abnormal are not available.

    Gonadotropin Levels in Certain Conditions Associated With Primary Amenorrhea or Delayed Puberty
    FSH and LH decreased*
    Hypopituitarism
    Hypothalamic dysfunction
    Constitutional delayed puberty
    Some cases of primary hypothyroidism
    Some cases of Cushing’s syndrome
    Some cases of severe chronic illness
    FSH and LH increased†
    Some cases of congenital adrenal hyperplasia
    Female gonadal dysgenesis
    Male gonadal dysgenesis
    Ovarian failure due to nonovarian agents
    LH increased, FSH not increased‡
    Testicular feminization
    Some cases of PCO disease

    Elevated FSH and LH levels or an elevated LH level alone suggests primary ovarian failure, whether from congenital absence of the ovaries or congenital inability to respond to gonadotropins, acquired abnormality such as damage to the ovaries after birth, or PCO disease.

    An elevated estrogen or androgen level raises the question of hormone-secreting tumor, for which the ovary is the most common (but not the only) location. Nontumor androgen production may occur in PCO disease and Cushing’s syndrome (especially adrenal carcinoma).

    As noted previously, there is no universally accepted single standard method to investigate female reproductive disorders. Tests or test sequences vary among medical centers and also according to findings in the individual patients.

    When specimens for pituitary hormone assays are collected, the potential problems noted earlier in the chapter should be considered.

  • Adrenal and Nonadrenal Causes of Hypertension

    Cushing’s syndrome, primary aldosteronism, unilateral renal disease (rarely, bilateral renal artery stenosis), and pheochromocytoma often produce hypertension. Hypertension due to these diseases is classified as secondary hypertension, in contrast to primary idiopathic (essential) hypertension. Although patients with these particular diseases that cause secondary hypertension are a relatively small minority of hypertension patients, the diseases are important because they are surgically curable. The patient usually is protected against the bad effects of hypertension by early diagnosis and cure. Patients who must be especially investigated are those who are young (less than age 50 years), those whose symptoms develop over a short time, or those who have a sudden worsening of their hypertension after a previous mild stable blood pressure elevation.

  • Cushing’s Syndrome. Part 2

    48-hour dexamethasone suppression test.

    The 48-hour DST is the most widely used confirmatory procedure. Dexamethasone (Decadron) is a synthetic steroid with cortisone-like actions but is approximately 30 times more potent than cortisone, so that amounts too small for laboratory measurement may be given to suppress pituitary ACTH production. The test is preceded by two consecutive 24-hour urine collections as a baseline. If low doses (2 mg/day) are used, patients with normal adrenal function usually have at least a 50% decrease (suppression) in their 24-hour urine 17-OHCS values compared to baseline, whereas those with Cushing’s syndrome from any etiology have little if any change. This test result is usually normal in those patients whose low-dose overnight DST is abnormal (nonsuppressed) only because of obesity. If larger doses (8 mg/day) are used, about 85% (range, 42%-98%) of those with adrenal cortex hyperplasia due to pituitary oversecretion of ACTH have at least a 50% decrease (suppression) of their 24-hour urine 17-OHCS values. Adrenal cortisol-producing adenomas or carcinoma rarely decrease their urine 17-OHCS levels. Patients with the ectopic ACTH syndrome due to bronchial or thymus carcinoids have been reported to produce false positive test results (decrease in urine 17-OHCS levels) in up to 40% of patients. Patients with the ectopic ACTH syndrome from lung small cell carcinoma or other tumors rarely change urine 17-OHCS levels. Since the test takes a total of 4 days (48 hours at baseline and 48 hours of test duration) and requires 24-hour urine collections, and since there are a significant number of exceptions to the general rules, plasma ACTH assay is supplementing or replacing the high-dose DST for differentiation of the various etiologies of Cushing’s syndrome. Some investigators report that the metyrapone test (discussed later) is better than the 48-hour high-dose DST in differentiating pituitary oversecretion of ACTH from adrenal tumor.

    A single-dose overnight version of the high-dose DST has been reported, similar to the low-dose overnight test. A baseline serum cortisol specimen is drawn fasting at 8 A.M.; 8 mg of dexamethasone is given at 11 P.M.; and a second serum cortisol specimen is drawn fasting at 8 A.M. the next day. Normal persons and patients with pituitary ACTH syndrome have 50% or more cortisol decrease from baseline. Cortisol-producing adrenal tumors and ectopic ACTH patients have little change. Limited evaluation of this test reported similar results to the standard high-dose dexamethasone procedure.

    Metyrapone test. Metyrapone (Metopirone) blocks conversion of compound S to cortisol. This normally induces the pituitary to secrete more ACTH to increase cortisol production. Although production of cortisol is decreased, the compound S level is increased as it accumulates proximal to the metyrapone block, and 17-OHCS or radioassay CPB methods for cortisol in either serum or urine demonstrate sharply increased apparent cortisol values (due to compound S) in normal persons and those with pituitary-induced adrenal cortex hyperplasia. Fluorescent assay or RIA for cortisol do not include compound S and therefore yield decreased cortisol values. Adrenal tumors are not significantly affected by metyrapone. Some authorities recommend measuring both cortisol and compound S. An increase in compound S verifies that lowering of the plasma cortisol level was accompanied by an increase in ACTH secretion. This maneuver also improves the ability of the test to indicate the status of pituitary reserve capacity, and the test is sometimes used for that purpose rather than investigation of Cushing’s disease. To obtain both measurements, one must select a test method for cortisol that does not also measure compound S. Compound S can be measured by a specific RIA method. Phenytoin or estrogen administration interferes with the metyrapone test.

    Adrenocorticotropic hormone stimulation test. Injection of ACTH directly stimulates the adrenal cortex. Patients with cortex hyperplasia and some adenomas display increased plasma cortisol and 17-OHCS levels. If urine collection is used, a 24-hour specimen taken the day of ACTH administration should demonstrate a considerable increase from preinfusion baseline values, which persists in a 24-hour specimen collected the day after ACTH injection. Normal persons should have increased hormone excretion the day ACTH is given but should return to normal in the next 24 hours. Carcinoma is not affected. The ACTH stimulation test at present does not seem to be used very frequently.

    Serum adrenocorticotropic hormone. Serum ACTH measurement by immunoassay is available in many reference laboratories. At present, the assay techniques are too difficult for the average laboratory to perform in a reliable fashion, and even reference laboratories still have problems with accuracy.

    There is a diurnal variation in serum ACTH levels corresponding to cortisol secretion, with highest values at 8-10 A.M. and lowest values near midnight. Stress and other factors that affect cortisol diurnal variation may blunt or eliminate the ACTH diurnal variation. Serum ACTH data in adrenal disease are summarized in Table 30-1.

    Plasma adrenocorticotropic hormone in adrenal diseases

    Table 30-1 Plasma adrenocorticotropic hormone in adrenal diseases

    In Cushing’s syndrome due to adrenal tumor or micronodular hyperplasia, pituitary activity is suppressed by adrenal-produced cortisol, so the serum ACTH level is very low. In ectopic ACTH syndrome, the serum ACTH level is typically very high (4-5 times the upper preference limit) due to production of cross-reacting ACTH-like material by the tumor. However, some patients with the ectopic ACTH syndrome have serum levels that are not this high. In bilateral adrenal hyperplasia due to pituitary overactivity, serum ACTH levels can either be normal or mildly to moderately elevated (typically less than the degree of elevation associated with the ectopic ACTH syndrome). However, there is a substantial degree of overlap between pituitary tumor ACTH values and ectopic ACTH syndrome values. It has been suggested that ACTH specimens obtained at 10-12 P.M. provide better separation of normal from pituitary hypersecretion than do specimens drawn in the morning. Another study found that specimens drawn between 9:00 and 9:30 A.M. provided much better separation of normal from pituitary hypersecretion than specimens drawn at any other time in the morning. In summary, adrenal tumor (low ACTH levels) can usually be separated from pituitary-induced adrenal cortex hyperplasia (normal or increased ACTH levels) and from ectopic ACTH (increased ACTH levels). Pituitary-induced adrenal cortex hyperplasia has ACTH values that overlap with the upper range of normal persons and with the lower range of the ectopic ACTH syndrome. The time of day that the specimen is drawn may improve separation of normal persons from those with Cushing’s disease.

    Corticotropin-releasing hormone test. About 85% of Cushing’s disease is due to pituitary hyperplasia or tumor, and about 15% is due to ectopic ACTH from a nonpituitary tumor. Corticotropin-releasing hormone (CRH) from the hypothalamus stimulates the pituitary to release ACTH (corticotropin). Ovine CRH is now available, and investigators have administered this hormone in attempts to differentiate adrenal tumor and the ectopic ACTH syndrome from pituitary overproduction of ACTH. Initial studies reported that after CRH administration, pituitary ACTH-producing tumors increased plasma cortisol levels at least 20% over baseline and increased their ACTH level at least 50% over baseline. Normal persons also increase their ACTH and plasma cortisol levels in response to CRH, and there is substantial overlap between normal response and pituitary tumor response. Primary adrenal tumors and the ectopic ACTH syndrome either did not increase cortisol levels or increased ACTH less than 50% and plasma cortisol levels less than 20%. However, several studies found that about 10% of pituitary ACTH-producing tumors failed to increase plasma ACTH or cortisol to expected levels. This is similar to the rate that pituitary tumors fail to suppress cortisol production as much as expected in the high-dose 48-hour DST. About 15% of patients with the ectopic ACTH syndrome overlap with pituitary ACTH tumors using the ACTH criteria already mentioned, and about 10% overlap using the plasma cortisol criteria. Therefore, differentiation of the etiologies of Cushing’s syndrome by the CRH test alone is not as clear-cut as theoretically would be expected. To prevent false results, the patients should not be under therapy for Cushing’s syndrome when the test is administered.

    The CRH test has also been advocated to evaluate the status of pituitary function in patients on long-term, relatively high-dose corticosteroid therapy.

    To summarize, the expected results from the CRH test after injection of CRH are (1) for a diagnosis of Cushing’s disease, an exaggerated response from adenoma of pituitary; (2) for Cushing’s syndrome of adrenal origin or ectopic ACTH syndrome, no significant increase in ACTH; (3) for the differential diagnosis of increased ACTH from pituitary microadenoma versus ectopic ACTH syndrome, inconsistent results. The CRH test is not completely reliable in differentiating primary pituitary disease from hypothalamic deficiency disease.

    Cushing’s disease versus ectopic ACTH syndrome. The intracerebral inferior venous petrosal sinuses receive the venous blood from the pituitary containing pituitary-produced hormones; the right inferior petrosal sinus mostly from the right half of the pituitary and the left sinus from the left half. Several studies have suggested that catheterization of both inferior petrosal sinuses can differentiate ectopic ACTH production from the pituitary ACTH overproduction of Cushing’s disease in patients who do not show a pituitary tumor on computerized tomography (CT) scan or when the diagnosis is in question for other reasons. The most commonly used method is comparison of the ACTH level in the inferior petrosal sinuses with peripheral venous blood (IPS/P ratio) 3 minutes after pituitary stimulation by ovine CRH. Although several criteria have been proposed, it appears that an IPS/P ratio greater than 2.0 without CRH stimulation or a ratio of 3.3 or more in one of the inferior petrosal sinuses 3 minutes after CRH stimulation is over 95% sensitive and specific for Cushing’s disease versus ectopic ACTH syndrome (if technical problems are avoided). However, apparently this procedure is not as good in differentiating Cushing’s disease from pseudo-Cushing’s disease, since there is about 20% overlap with results from patients with some clinical or laboratory findings suggestive of Cushing’s disease (such as some patients with psychiatric depression) but without proof of pituitary hyperplasia or adenoma. In one study the same overlap was seen with clinically normal persons.

    Computerized tomography

    CT can frequently differentiate between unilateral adrenal enlargement (adrenal adenoma or carcinoma) and bilateral enlargement (pituitary hyperactivity or ectopic ACTH syndrome). However, it has been reported that nonfunctioning adrenal cortex nodules may occur in 1%-8% of normal persons, and one of these nodules could be present coincidentally with pituitary Cushing’s syndrome or ectopic ACTH. CT is very useful, better than pituitary sella x-ray films, in verifying the presence of a pituitary adenoma. Even so, third- and fourth-generation CT detects only about 45% (range, 30%-60%) of pituitary adenomas. In addition, it has been reported that 10%-25% of normal persons have a pituitary microadenoma, and some of these nonfunctioning nodules may be seen on CT and lead to a misdiagnosis of Cushing’s disease.

    Summary of tests in Cushing’s syndrome

    Currently, the most frequently utilized tests to screen for Cushing’s syndrome are the overnight low-dose DST and the test to detect abolishment of serum cortisol diurnal variation. Urine free-cortisol determination would provide more accurate information than the diurnal variation test. Confirmatory tests (if necessary) and tests to differentiate adrenal from nonadrenal etiology that are most often used are the 48-hour DST or the metyrapone test, serum ACTH assay, and CT visualization of the adrenals.

    Conditions that affect the screening and confirmatory tests should be kept in mind. In particular, alcoholism (especially with recent drinking) and psychiatric depression can closely mimic the test results that suggest Cushing’s syndrome. Finally, there are some patients in each category of Cushing’s syndrome etiology who do not produce the theoretically expected response to screening or confirmatory tests.

  • Cushing’s Syndrome. Part 1

    Cushing’s syndrome is caused by excessive body levels of adrenal glucocorticoids such as cortisol, either from (primary) adrenal cortex overproduction or from (secondary) therapeutic administration. This discussion will consider only the primary type due to excess adrenal production of cortisol. About 70% of cases (range 50%-80%) of Cushing’s syndrome due to adrenal overproduction of cortisol are caused by pituitary hypersecretion of ACTH leading to bilateral adrenal cortex hyperplasia. About 10% of cases are due to adrenal cortex adenoma, about 10% to adrenal cortex carcinoma, and about 10% to “ectopic” ACTH production by tumors outside the adrenal or pituitary glands, most commonly lung bronchial carcinoids (28%-38% of ectopic tumor cases) with the next most frequent being lung small cell carcinomas. A few cases are caused by thymus carcinoids, pancreatic islet cell tumors, pheochromocytomas, and various adenocarcinomas. One additional category is the uncommon syndrome of micronodular cortical hyperplasia, which biochemically behaves in a similar manner to adrenal cortex adenoma. Adrenal tumor is the most frequent etiology in patients younger than 10 years, and pituitary hyperactivity is the most common cause in patients older than 10. Cushing’s syndrome must be differentiated from Cushing’s disease, which is the category of Cushing’s syndrome due to pituitary hypersecretion of ACTH (usually due to a basophilic cell pituitary adenoma or microadenoma). The highest incidence of Cushing’s syndrome is found in adults, with women affected 4 times more often than men. Major symptoms and signs include puffy, obese-looking (“moon”) appearance of the face, body trunk obesity, “buffalo hump” fat deposit on the back of the neck, abdominal striae, osteoporosis, and a tendency to diabetes, hirsutism, easy bruising, and hypertension.

    Standard test abnormalities

    General laboratory findings include impairment of glucose tolerance in about 85% of patients (literature range, 57%-94%) that is severe enough to be classified as diabetes mellitus in about 25%. There is lymphocytopenia (usually mild) in about 80%, but most patients have an overall mild leukocytosis. Hemoglobin tends to be in the upper half of the reference range, with polycythemia in about 10% of affected persons. About 20%-25% have a mild hypokalemic alkalosis. The serum sodium level is usually normal but is slightly increased in about 5%. Total circulating eosinophils are usually decreased.

    Screening tests

    Urine 17-Ketosteroid assay. The urine 17-KS assay was one of the first tests used for diagnosis of Cushing’s syndrome. However, urine 17-KS values are increased in only about 50%-55% of patients with Cushing’s syndrome, and the test yields about 10% false positive results. Thus, 17-KS assay is no longer used to screen for Cushing’s syndrome. The 17-KS values may be useful in patients who are already known to have Cushing’s syndrome. About 45% of patients with adrenal adenoma and about 80%-85% (range 67%-91%) of patients with adrenal carcinoma have elevated urine 17-KS values. Patients with adrenal carcinoma tend to have higher urine 17-KS values than patients with Cushing’s syndrome from other etiologies, so that very high urine 17-KS values of adrenal origin suggest adrenal carcinoma.

    Single-specimen serum cortisol assay. Laboratory diagnosis of Cushing’s syndrome requires proof of cortisol hypersecretion. For some time, assay of 17-OHCS in a 24-hour urine specimen or a single-specimen plasma 17-OHCS assay by the Porter-Silber method was the mainstay of diagnosis. However, in Cushing’s syndrome this technique yields about 15% false negative and 15% false positive results. The 17-OHCS values in urine are increased in some patients by obesity, acute alcoholism, or hyperthyroidism, whereas the 17-OHCS values in plasma are increased in many patients by stress, obesity, or an increase in cortisol-binding protein due to estrogen increase (oral contraceptive medication or pregnancy). Therefore, urine 17-OHCS assay and single determinations of plasma 17-OHCS are no longer considered reliable enough to screen for Cushing’s syndrome. Plasma or urine 17-OHCS assay was also used to measure adrenal response in stimulation or suppression tests. However, it has been replaced for this purpose by serum cortisol assay, which is technically easier to do and avoids the many problems of 24-hour urine specimen collections.

    Single determinations of plasma cortisol, either in the morning or in the afternoon or evening, have the same disadvantages as plasma 17-OHCS and are not considered reliable for screening of Cushing’s syndrome. For example, single morning specimens detect about 65% of patients with Cushing’s syndrome (range, 40%-83%) and produce false positive results in about 30% of cases (range, 7%-60%). One report indicates that 11 P.M. or midnight specimens provide better separation of normal persons from those with Cushing’s syndrome.

    Plasma cortisol diurnal variation. If plasma cortisol assay is available, a better screening test for Cushing’s syndrome than a single determination consists of assay of two plasma specimens, one drawn at 8 A.M. and the other at 8 P.M. Normally there is a diurnal variation in plasma levels (not urine levels), with the highest values found between 6 and 10 A.M. and the lowest near midnight. The evening specimen ordinarily is less than 50% of the morning value. In Cushing’s syndrome, diurnal variation is absent in about 90% of patients (literature range, 70%-100%). False positive results are obtained in about 20% of patients (range, 18%-25%). Therefore, significant alteration of the diurnal pattern is not specific for Cushing’s syndrome, since it is found occasionally in patients with a wide variety of conditions. Some of the conditions that may decrease or abolish the normal drop in the evening cortisol level in some persons are listed in the box on this page. Therefore, a normal result (normal circadian rhythm) is probably more significant than an abnormal result (although, as already noted normal plasma cortisol circadian rhythm may be present in about 10% of patients with Cushing’s syndrome).

    Urine free cortisol. About 1% of plasma cortisol is excreted by the kidney in the original free or unconjugated state; the remainder appears in urine as conjugated metabolites. Original Porter-Silber chromogenic techniques could not measure free cortisol selectively. Fluorescent methods or immunoassay can quantitate free cortisol, either alone or with compound S, depending on the method. Immunoassay is becoming the most frequently used technique. Urine free-cortisol values in 24-hour collections are reported to be elevated in about 95% of patients with Cushing’s syndrome (literature range, 90%-100%) and to produce false positive elevation in about 6% of patients without Cushing’s syndrome (literature range, 0%-8%).

    Urine free-cortisol levels may be elevated in some patients by some of the factors that affect blood cortisol, including severe stress, acute alcoholism, psychiatric depression, and occasionally patients with obesity. In cortisol-binding protein changes such as an increase produced by estrogens, most reports indicate that urine free-cortisol secretion levels are usually normal. Renal insufficiency may elevate plasma cortisol levels and decrease urine free-cortisol levels. Hepatic disease may increase plasma cortisol levels but usually does not affect urine free-cortisol levels significantly. The major difficulty with the test involves accurate collection of the 24-hour specimen. Also, the test is not performed in most ordinary laboratories and would have to be sent to a medical center or reference laboratory.

    Some Conditions That Affect Serum Cortisol Diurnal Variation

    Severe stress
    Severe nonadrenal illness
    Obesity
    Psychiatric depression
    Alcoholism (especially with recent intake)
    Change in sleep habits
    Encephalitis
    Blindness
    Certain medications (prolonged steroids, phenothiazines, reserpine, phenytoin, amphetamines)

    Single-dose dexamethasone suppression test. The most simple reasonably accurate screening procedure is a rapid overnight dexamethasone suppression test (DST). Oral administration of 1 mg of dexamethasone at 11 P.M. suppresses pituitary ACTH production, so that the normal 8 A.M. peak of plasma cortisol fails to develop. After 11 P.M. dexamethasone, normal persons and the majority of obese persons have 8 A.M. plasma cortisol values less than 50% of baseline (predexamethasone) levels. Many endocrinologists require suppression to 5 µg/100 ml (138 nmol/L) or less. The consensus is that about 95% of Cushing’s syndrome patients exhibit abnormal test response (failure to suppress), although there is a range in the literature of 70%-98%). There is an average of less than 5% false positive results in normal control persons (range, 1%-10%).

    There is controversy in the literature regarding certain aspects of this test. Some investigators found substantial numbers of patients with a Cushingoid type of obesity, but without demonstrable Cushing’s syndrome, who failed to suppress adequately (falsely suggesting Cushing’s syndrome) after the overnight DST. This involved 10% of Cushingoid obese patients in one series and 53% in another. Unfortunately, there are not many reports in the literature that differentiate lean from obese persons in control series. Another controversial point is the degree that the 8 A.M. cortisol specimen must be suppressed from baseline value to separate normal persons from those with Cushing’s syndrome. Some have found the standard of a 50% decrease from baseline values to be insufficiently sensitive, missing up to 30% of Cushing’s syndrome patients. These investigators suggest a fixed 8 A.M. plasma cortisol value (after dexamethasone) of 5 or 7 µg/100 ml. However, establishment of such a fixed value is complicated by the variations in cortisol reference ranges found in different methods and kits. Another problem are conditions that may produce false results (failure to suppress normally). Some of these are listed in the box on this page.

    Phenytoin and phenobarbital affect cortisol by affecting the microsomal metabolic pathway of the liver. Estrogen increases cortisol-binding protein values, which, in turn, increases total plasma cortisol values. This may affect the DST when a fixed 5 µg/100 ml cutoff limit is used, since the already increased cortisol level must be suppressed even more than usual to reach that value. Spironolactone is a fluorescent compound and interferes with the Mattingly fluorescent assay technique. Immunoassay is not affected. Additional evidence to support abnormal screening test results may be obtained by using the standard DST.

    Some Conditions That Interfere With the Low-Dose Overnight Dexamethasone Suppression Test

    Conditions producing false normal test results*
    Drug-induced interference (phenytoin, phenobarbital, estrogens, possibly spironolactone)
    Conditions producing false abnormal test results†
    Acute alcoholism
    Psychiatric depression
    Severe stress
    Severe nonadrenal illness
    Malnutrition
    Obesity (some patients)
    Renal failure
    _____________________________________________________________
    * Apparent suppression of 8 A.M. cortisol in patients with Cushing’s syndrome.
    † Failure to suppress 8 A.M. cortisol in patients without Cushing’s syndrome.

    The single-dose DST and diurnal variation test may be combined. Plasma cortisol specimens are drawn at 8 A.M. and 8 P.M. Dexamethasone is administered at 11 P.M., followed by a plasma cortisol specimen at 8 A.M. the next day.

    Confirmatory tests

    Confirmation of the diagnosis depends mainly on tests that involve either stimulation or suppression of adrenal hormone production. It is often possible with the same tests to differentiate the various etiologies of primary hyperadrenalism. Normally, increased pituitary ACTH production increases adrenal corticosteroid release. Increased plasma corticosteroid levels normally inhibit pituitary release of ACTH and therefore suppress additional adrenal steroid production. Adrenal tumors, as a rule, produce their hormones without being much affected by suppression tests; on the other hand, they tend to give little response to stimulation, as though they behaved independently of the usual hormone control mechanism. Also, if urinary 17-KS values are markedly increased (more than twice normal), this strongly suggests carcinoma. However, hyperplasia, adenoma, and carcinoma values overlap, and 17-KS levels may be normal with any of the three etiologies.

  • Effects of Adrenal Cortex Dysfunction

    Certain adrenal cortex hormones control sodium retention and potassium excretion. Aldosterone is the most powerful of these hormones, but cortisone and hydrocortisone also have some effect. In primary Addison’s disease there are variable degrees of adrenal cortex destruction. This results in deficiency of both aldosterone and cortisol, thereby severely decreasing normal salt-retaining hormone influence on the kidney. Sometimes there is just enough hormone to maintain sodium balance at a low normal level. However, when placed under sufficient stress of any type, the remaining adrenal cortex cells cannot provide a normal hormone response and therefore cannot prevent a critical degree of sodium deficiency from developing. The crisis of Addison’s disease is the result of overwhelming fluid and salt loss from the kidneys and responds to adequate replacement. Serum sodium and chloride levels are low, the serum potassium level is usually high normal or elevated, and the patient is markedly dehydrated. The carbon dioxide (CO2) content may be normal or may be slightly decreased due to the mild acidosis that accompanies severe dehydration. In secondary Addison’s disease, due to pituitary insufficiency, glucocorticoid hormone production is decreased or absent but aldosterone production is maintained. However, hyponatremia sometimes develops due to an increase in AVP (ADH) production by the hypothalamus. In primary aldosteronism there is oversecretion of aldosterone, which leads to sodium retention and potassium loss. However, sodium retention is usually not sufficient to produce edema, and the serum sodium value remains within the reference range in more than 95% of cases. The serum potassium value is decreased in about 80% of cases (literature range, 34%-92%). In Cushing’s syndrome there is overproduction of hydrocortisone (cortisol), which leads to spontaneous mild hypokalemia and hypochloremic alkalosis in 10%-20% of patients (usually those with more severe degrees of cortisol excess). Use of diuretics will induce hypokalemia in other patients. The serum sodium level usually remains within reference range.